Periconceptional
folic acid supplementation reduces the risk of
neural tube defects (NTDs). To determine whether periconceptional exposure to
folic acid antagonists (FAAs) might therefore increase the risk of NTDs, the authors examined data from an ongoing case-control study of
birth defects (1979-1998) in the United States and Canada. They compared data on 1,242 infants with NTDs (
spina bifida,
anencephaly, and
encephalocele) with data from a control group of 6,660 infants with malformations not related to
vitamin supplementation. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors and about medication use. The adjusted odds ratios of NTDs related to exposure to FAAs (including
carbamazepine,
phenobarbital,
phenytoin,
primidone,
sulfasalazine,
triamterene, and
trimethoprim) during the first or second months after the last menstrual period, compared with no use in either month, were 2.8 (95% confidence interval: 1.7, 4.6) for FAAs as a group, 4.8 (95% confidence interval: 1.5, 16.1) for
trimethoprim (based on five exposed cases), and 6.9 (95% confidence interval: 1.9, 25.7) for
carbamazepine (six exposed cases). These results are adjusted for region, interview year, periconceptional
folic acid supplementation, maternal age, weight, education, and
infections early in pregnancy. These findings suggest that a number of FAAs may increase NTD risk, and they provide estimates of risk for selected drugs.